Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Programmed cell death (apoptosis) is an active process by which cells initiate their own self-destruction. Growing evidence shows that this event is controlled by the activation of unique gene expression; some function as survival genes, such as bcl2, and others as killer genes, such as ced3 or interleukin converting enzyme. Likewise, external factors, such as the presence or absence of stimuli in the microenvironment of a cell, play a key role in ushering it towards survival or suicidal fate. Previously, I and others have reported that withdrawal of serum from culture medium can induce contact-inhibited quiescent mouse 3T3 fibroblasts to undergo rapid programmed cell death, as evidenced by the presence of massive DNA fragmentation within 24 h. I now report that, although the same process of serum withdrawal is capable of inducing apoptotic death in quiescent young human fibroblasts, the process takes as long as 2 weeks. Repeated attempts at the same serum withdrawal with cultures of senescent human fibroblasts show that phenotypic signs of apoptosis, such as DNA fragmentation and loss of cell viability, are not observed for up to 4 weeks; I suggest that in vitro aged human fibroblasts are resistant to undergoing programmed cell death. I have investigated the level of bcl2 presence as a possible protector of senescent human fibroblasts from apoptotic death; biochemical characterization shows that in mouse as well as human fibroblasts, bcl2 is present as an easily extractable (0.1% Triton) cytoplasmic protein. bcl2 level is in inverse relationship with the ease of induction of apoptotic death between young and senescent human fibroblasts. Immunofluorescence staining shows that, in senescent human fibroblasts, bcl2 is present not only in the cytoplasmic punctate spots seen in both mouse and young human fibroblasts but also in the nuclei as well as large granules surrounding the nuclei. Upon serum deprivation, the bcl2 level is reduced to undetectable in mouse 3T3 fibroblasts within 24 h and in young and intermediate aged human fibroblasts within 2 weeks; however, it remains unchanged in senescent human fibroblasts after the deprivation of serum for 2 weeks. These findings lead me to conclude that senescent fibroblasts are resistant to the induction of apoptotic death by serum deprivation. Furthermore, I suggest that repeated serial passaging during the in vitro aging process has inadvertently instituted a molecular mechanism whereby the bcl2 level cannot be repressed upon serum deprivation, which may subsequently allow senescent fibroblasts to be long-lived and protected from self-destruction.
 ...
PMID:Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. 775 77

Apoptosis is the physiological process by which unwanted cells in an organism are killed. Bcl-2, a membrane-bound cytoplasmic protein, is an effective inhibitor of apoptotic cell death induced by many cytotoxic agents. Survival-promoting homologues of Bcl-2 include its close relative, Bcl-xL and the 19 kD protein encoded by the E1B gene of adenoviruses. Whether these proteins are functionally equivalent and whether they can antagonise all or only some pathways to apoptosis is unresolved. We have carried out a systematic comparison of Bcl-2, Bcl-xL and adenovirus E1B19kD activity, using several cell lines and a range of cytotoxic conditions. High levels of expression of each of these proteins inhibited apoptosis induced by growth factor deprivation or treatment with gamma-radiation, glucocorticoid and various cytotoxic drugs. In contrast, none of them could effectively counter apoptosis induced via the TNF receptor or Fas/APO-1 (CD95). Biochemical analysis revealed that all three proteins can associate with Bax and Bak, members of the Bcl-2 protein subfamily that can facilitate apoptosis. The results provide evidence that Bcl-2, Bcl-xL and adenovirus protein E1B19kD are indistinguishable in their ability to regulate the cell death effector machinery.
 ...
PMID:Bcl-2, Bcl-XL and adenovirus protein E1B19kD are functionally equivalent in their ability to inhibit cell death. 905 37

Apoptosis is the physiological process by which unwanted cells in an organism are killed. Bcl-2, a membrane-bound cytoplasmic protein, and its close relative Bcl-xL, are both effective inhibitors of apoptosis induced by a wide variety of stimuli in many different cell types. In a previous study, we reported that suppression of apoptosis by Bcl-2 or Bcl-xL, markedly elevates the levels of radiation-induced mutations at the specific locus thymidine kinase. We investigated the effect of the Bcl-2 or Bcl-xL overproduction on hydrogen peroxide-induced mutagenesis. Oxidative DNA damage has been implicated in biological processes such as mutagenesis, carcinogenesis and aging. Overexpression of either Bcl-2 or Bcl-xL enhances oxidative stress mutagenesis in cells with wild type p53 as well as with mutated p53 protein. These results support the hypothesis that apoptosis plays a crucial role in maintaining genomic integrity by selectively eliminating highly mutated cells from the population.
 ...
PMID:Suppression of apoptosis by overexpression of Bcl-2 or Bcl-xL promotes survival and mutagenesis after oxidative damage. 946

Bcl-2 is a cytoplasmic protein that blocks apoptosis in a wide variety of cell types. Here we report a novel role for Bcl-2 in the early stages of neuronal development. Shortly after differentiating from progenitor cells, sensory neurons undergo a distinct morphological change; initially they have small, spindle-shaped, phase-dark cell bodies that become large, spherical, and phase-bright. Early sensory neurons cultured from the trigeminal ganglia of bcl-2-/- embryos at embryonic day 11 (E11) and E12 underwent this change more slowly than trigeminal neurons of wild-type embryos of the same ages. The delay was not attributable to the well documented role of Bcl-2 in preventing apoptosis, because Bcl-2-deficient early sensory neurons survived as well as wild-type neurons. Accordingly, there was a significantly smaller number of the more mature type of neuron in the early trigeminal ganglia of bcl-2-/- embryos, yet the number of neurons in the trigeminal ganglia of bcl-2-/- and wild-type embryos was similar. The absence of Bcl-2 did not cause a uniform delay in the developmental program of sensory neurons, because the time course of nerve growth factor receptor expression (both trkA and p75) was unaffected in the trigeminal neurons of bcl-2-/- embryos. These findings indicate that Bcl-2 expression is required for the normal progression of a particular early maturational change in embryonic sensory neurons.
 ...
PMID:Bcl-2 accelerates the maturation of early sensory neurons. 954 42

The major vault lung resistance protein LRP is a cytoplasmic protein involved in drug resistance, especially in acute myeloid leukemia. We looked for LRP overexpression, using immunocytochemistry with LRP 56 monoclonal antibody, on marrow slides from 41 cases of myelodysplastic syndromes (MDS). LRP overexpression (LRP+) was defined by expression of LRP 56 in at least 20% of marrow blasts. LRP overexpression was seen in 19 (46%) cases. Concordant results between LRP overexpression and P-glycoprotein (PGP) expression were seen in 66% of the cases (p = 0.03), and discordant results (LRP+ and PGP-, or LRP- and PGP+) in 33% of the cases. No correlation was seen between LRP overexpression and FAB type, karyotype, CD34, p53 expression and bcl2 overexpression in blasts. Furthermore, in the 18 cases treated with anthracycline-AraC intensive chemotherapy and the 7 cases treated with low dose AraC, the response rate was not significantly different in LRP+ and LRP- patients. Survival was also similar in LRP+ and LRP- patients. In conclusion, LRP overexpression is probably more frequent in MDS than in de novo AML and, as in AML, is only partially correlated with PGP expression. In our experience, however, LRP was not a prognostic factor for response to chemotherapy and survival in MDS.
 ...
PMID:Expression of lung resistance protein and correlation with other drug resistance proteins and outcome in myelodysplastic syndromes. 964 68

By making use of receptor-Ck positive lymphocytes (from normal human subjects) as well as receptor-Ck negative lymphocytes (from untreated chronic myeloid leukemic (CML) patients) as cellular models, we were able to show that receptor-Ck-dependent signalling is involved in the regulation of genes coding for Bcl-2 and cyclin D. Further, experiments directed to resolve the mechanism by which this receptor regulates these genes revealed that receptor-Ck, upon activation by cholesterol, initiates the cleavage of a 125 kDa cytoplasmic protein leading to the generation of a 47 kDa factor having specific affinity for genomic sterol regulatory element (SRE)/SRE-like sequence present in the promoter region of genes coding for Bcl-2 and cyclin D. Based upon these observations, we propose that the inability of leukemic cells to express receptor-Ck is responsible for the deregulated over-expression of genes coding for Bcl-2 and cyclin D and this phenomenon may be of importance in understanding leukemic haematopoiesis.
 ...
PMID:Receptor-Ck controls the expression of Bcl-2 and cyclin d genes. 968 93

Recruitment of the SH2 domain containing cytoplasmic protein-tyrosine phosphatase SHP-1 to the membrane by somatostatin (SST) is an early event in its antiproliferative signaling that induces intracellular acidification-dependent apoptosis in breast cancer cells. Fas ligation also induces acidification-dependent apoptosis in a manner requiring the presence of SHP-1 at the membrane. Moreover, we have recently reported that SHP-1 is required not only for acidification, but also for apoptotic events that follow acidification (Thangaraju, M., Sharma, K., Liu, D., Shen, S. H., and Srikant, C. B. (1999) Cancer Res. 59, 1649-1654). Here we show that ectopically expressed SHP-1 was predominantly membrane-associated and amplified the cytotoxic signaling initiated upon SST receptor activation and Fas ligation. The catalytically inactive mutant of SHP-1 (SHP-1C455S) abolished the ability of the SST agonists to signal apoptosis by preventing the recruitment of wild type SHP-1 to the membrane. Overexpression of the anti-apoptotic protein Bcl-2 in MCF-7 cells inhibited SST-induced apoptosis upstream of acidification by inhibiting p53-dependent induction of Bax as well as by raising the resting pH(i) and attenuating SST-induced decrease in pH(i). By contrast, Bcl-2 failed to prevent apoptosis triggered by direct acidification. These data demonstrate that (i) membrane-associated SHP-1 is required for receptor-mediated cytotoxic signaling that causes intracellular acidification and apoptosis, and (ii) Bcl-2 acts distal to SHP-1 and p53 to prevent SST-induced acidification but cannot inhibit the apoptotic events that ensue intracellular acidification.
 ...
PMID:Regulation of acidification and apoptosis by SHP-1 and Bcl-2. 1050 21

Bax is a proapoptotic member of the Bcl-2 protein family that commits the cell to undergo programmed cell death in response to apoptotic stimuli. To gain further insights into Bax mechanisms, we have identified a novel Bax-binding protein, termed Bif-1, by using a yeast two-hybrid cloning technique. Bif-1 is an evolutionarily conserved cytoplasmic protein that contains a predicted Src homology 3 (SH3) domain located near its C terminus but shares no significant homology with members of the Bcl-2 family. A Northern blot analysis indicates that Bif-1 is expressed in most tissues with abundant expression in heart and skeletal muscle. Bif-1 is capable of interacting with Bax as demonstrated by yeast two-hybrid, coimmunoprecipitation, and immunofluorescence studies. Induction of apoptosis in murine pre-B hematopoietic cells FL5.12 by interleukin-3 withdrawal results in increased association of Bax with Bif-1, which is accompanied by a conformational change in the Bax protein. Overexpression of Bif-1 promotes Bax conformational change, caspase activation, and apoptotic cell death in FL5.12 cells following interleukin-3 deprivation. Bif-1 thus represents a new type of regulator of Bax-mediated signaling pathways for apoptosis.
 ...
PMID:Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax. 1125 40

CED-9 blocks programmed cell death (apoptosis) in the nematode C. elegans by binding to and neutralizing CED-4, an essential activator of the aspartate-directed cysteine protease (caspase) CED-3. In mammals, the CED-9 homologs Bcl-2 and Bcl-xL also block apoptosis by interfering with the activation of CED-3-like caspases. However, it is unknown whether this occurs by binding to the CED-4 homolog Apaf-1. Whilst two groups previously detected an interaction between Bcl-xL and Apaf-1 in immunoprecipitates,1,2 another group found no interaction between Apaf-1 and any of ten individual members of the Bcl-2 family using the same experimental approach.3 In this study, we aimed to resolve this discrepancy by monitoring the binding of Apaf-1 to three Bcl-2 family members within cells. Using immunofluorescence and Western blot analysis, we show that whilst Apaf-1 is a predominantly cytoplasmic protein, Bcl-2, Bcl-xL and Bax mostly reside on nuclear/ER and mitochondrial membranes. This pattern of localization is maintained when the proteins are co-expressed in both normal and apoptotic cells, suggesting that Bcl-2, Bcl-xL or Bax do not significantly sequester cytoplasmic Apaf-1 to intracellular membranes. In addition, we confirm that Apaf-1 does not interact with Bcl-2 and Bcl-xL in immunoprecipitates. Based on these data, we propose that Apaf-1 is not a direct, physiological target of Bcl-2, Bcl-xL or Bax.
 ...
PMID:Failure of Bcl-2 family members to interact with Apaf-1 in normal and apoptotic cells. 1127 41

Immunohistochemical detection of expression of the anti-apoptotic Bcl-2 protein is widely studied as a putative prognostic and predictive factor in various types of cancer. For that purpose, heating for 10 min by microwave (MW) up t o 100 degrees C in citrate buffer, pH 6.0, prior to immunostaining is often used to retrieve Bcl-2 antigens in archival formalin-fixed, paraffin-embedded tissue. We recently reported that Bcl-2 is not only a cytoplasmic protein, but that it is present also in interphase nuclei and that it strongly associates with mitotic chromosomes. Furthermore, we showed that binding of the monoclonal antibody (MAb) #124 with nuclear/chromosomal epitopes is diminished by formaldehyde-based fixatives and cannot be restored by MW treatment for 10 min. Here we report that prolonged MW heating or heating up to 130 degrees C in a high pressure cooker (HPC), despite improved cytoplasmic immunostaining, fails to retrieve nuclear/chromosomal Bcl-2 epitopes recognized by the MAb #124 in human tissues. In contrast, these procedures can retrieve nuclear/chromosomal Bcl-2 epitopes detected by polyclonal #15616E antibodies in rat tissues. The specificity of these epitopes was confirmed by Western blot analysis of tissues treated by MW heating or HPC.
 ...
PMID:Comparison of the effects of microwave heating and high pressure cooking for antigen retrieval of human and rat Bc1-2 protein in formaldehyde-fixed, paraffin-embedded sections. 1222 34


1 2 Next >>